FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth

被引：42

作者：

Niu, Mengmeng ^{[1
]}

Xu, Jing ^{[1
]}

Liu, Yang ^{[1
]}

Li, Yuhuang ^{[1
]}

He, Tao ^{[1
]}

Ding, Liangping ^{[1
]}

He, Yajun ^{[1
]}

Yi, Yong ^{[1
]}

Li, Fengtian ^{[1
]}

Guo, Rongtian ^{[1
]}

Gao, Ya ^{[1
]}

Li, Rui ^{[1
]}

Li, Luping ^{[1
]}

Fu, Mengyuan ^{[1
]}

Hu, Qingyong ^{[1
]}

Luo, Yangkun ^{[1
]}

Zhang, Chunyan ^{[1
]}

Qin, Kewei ^{[1
]}

Yi, Jianqiao ^{[1
]}

Yu, Shuhan ^{[1
]}

Yang, Jian ^{[1
]}

Chen, Hu ^{[1
]}

Wang, Liang ^{[1
]}

Li, Zhonghan ^{[1
]}

Dong, Biao ^{[2
]}

Qi, Shiqian ^{[2
]}

Liang Ouyang ^{[2
]}

Zhang, Yujun ^{[1
]}

Cao, Yang ^{[1
]}

Xiao, Zhi-Xiong Jim ^{[1
,2
]}

机构：

[1] Sichuan Univ, Key Lab Bioresource & Ecoenvironm, Ctr Growth Metab & Aging, Minist Educ,Coll Life Sci, Chengdu, Peoples R China

[2] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu, Peoples R China

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

LUNG-CANCER; FACTOR-RECEPTOR; ACQUIRED-RESISTANCE; QUALITY-CONTROL; DEGRADATION; MUTATION; DOCKING; HSP90; UBIQUITINATION; ENDOCYTOSIS;

D O I：

10.1038/s41467-021-26222-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Abnormal activation of epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC) development. EGFR mutations-mediated resistance to tyrosine-kinase inhibitors (TKIs) is a major hurdle for NSCLC treatment. Here, we show that F-box protein FBXL2 targets EGFR and EGFR TKI-resistant mutants for proteasome-mediated degradation, resulting in suppression of EGFR-driven NSCLC growth. Reduced FBXL2 expression is associated with poor clinical outcomes of NSCLC patients. Furthermore, we show that glucose-regulated protein 94 (Grp94) protects EGFR from degradation via blockage of FBXL2 binding to EGFR. Moreover, we have identified nebivolol, a clinically used small molecule inhibitor, that can upregulate FBXL2 expression to inhibit EGFR-driven NSCLC growth. Nebivolol in combination with osimertinib or Grp94-inhibitor-1 exhibits strong inhibitory effects on osimertinib-resistant NSCLC. Together, this study demonstrates that the FBXL2-Grp94-EGFR axis plays a critical role in NSCLC development and suggests that targeting FBXL2-Grp94 to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC. Aberrant EGFR activation is commonly found in non-small cell lung cancer (NSCLC). Here the authors show that E3 ubiquitin ligase FBXL2 targets EGFR and EGFR tyrosine kinase inhibitor (TKI)-resistant mutants for proteasome-mediated degradation to inhibit EGFR-driven NSCLC growth and TKI resistance.

引用

页数：15

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